Physicians' Academy for Cardiovascular Education

Reduction of afterload with ivabradine in patients with chronic systolic heart failure

Literature - Reil JC, Tardif JC, Ford I et al. - J Am Coll Cardiol. 2013 Jul 26


Selective heart rate reduction with ivabradine unloads the left ventricle in heart failure patients.
 

Reil JC, Tardif JC, Ford I et al.
J Am Coll Cardiol. 2013 Jul 26. doi:pii: S0735-1097(13)02870-2. 10.1016/j.jacc.2013.07.027
 

Background

Isolated heart rate reduction with the If-channel inhibitor ivabradine improves the composite end point of heart failure hospitalisations and cardiovascular death in patients with systolic heart failure in sinus rhythm who have resting heart rate >70 bpm prior to therapy [1,2]. Quality of life was also improved by reducing heart rate with ivabradine [3]. The beneficial effects of ivabradine were related to the magnitude of heart rate reduction and to the absolute value of the lowest obtained heart rate [2]. The benefits were associated with left ventricular remodeling towards normal [4].
Although in experimental studies it has been shown that heart rate reduction ameliorates cardiac efficiency [5] and diastolic filling by prolonging diastole [6], it is unknown whether it can also reduce total afterload in humans. Interestingly, the effective arterial elastance (Ea), which integrates the mean and pulsatile load on the heart, depends on heart rate and total peripheral resistance directly [7,8]. Ivabradine improved aortic distensibility in animal models [10].
Thus, this study tested the hypothesis that isolated heart rate reduction with ivabradine reduces Ea by increasing vascular compliance, thereby unloading the left ventricle by improved ventricular-arterial interaction. Data from a subpopulation that participated in the echocardiographic substudie of the SHIFT study [4] were analysed (143 treated with ivabradine, 132 with placebo).
 

Main results

  • 8 months of ivabradine treatment was associated with a significantly decreased heart rate, as compared to placebo treatment (71+12 to 60+10 for ivabradine, vs. 71+11 to 68+12, P<0.0001). Pulse pressure, mean arterial pressure and end-systolic pressure did not differ significantly among treatment groups.
  • The ivabradine group also showed a significantly increased stroke volume, which was associated with a significant increase of TAC and a reduction of Ea, as compared to placebo.
  • LV end-diastolic volume (EDV) was significantly reduced as compared to baseline, but no difference was seen between ivabradine and placebo treatment. Both relative and absolute reduction of EDV were however significantly larger after ivabradine vs. placebo treatment.
  • End-systolic elastance (Ees), representing left ventricular contractility, was not different between ivabradine and placebo users.
  • The coupling ratio Ea/Ees, describing vascular-ventricular interaction, was similar at baseline in both groups. After 8 months of ivabradine, the ratio had decreased significantly as opposed to baseline (P<0.01), and in comparison to the placebo group (P<0.001).
  • A strong inverse correlation was seen between EF and the coupling ratio Ea/Ees at baseline (r=-0.77, P<0.001) and between the changes in EF and Ea/Ees seen in ivabradine treated patients (r=-0.63, P<0.001) and placebo treated patients (r=-0.61, P<0.001).
 

Conclusion

Isolated heart rate reduction with ivabradine significantly reduced the effective arterial elastance (Ea), which represents pulsatile and mean load of the left ventricle. The reduction of total afterload in these patients with chronic systolic heart failure is mostly the result of a lower vascular pulsatile load, indicated by larger total arterial compliance (TAC), while systemic vascular resistance remained stable. Improved TAC yields improved ventricular-arterial coupling with a significant increase in stroke volume, without affecting left ventricular contractility and cardiac output. Thus, unloading of the heart appears to be an underlying hemodynamic mechanism of isolated heart rate reduction, which may contribute to the beneficial outcome of treatment with ivabradine in patients with systolic heart failure.
 

Editorial comment [10]

This study provides evidence that HR reduction could be a strategy to treat HFrEF, by improving arterial loading and ventricular –arterial coupling without affecting peripheral resistance. Chronic treatment with ivabradine may improve pulsatile components of LV afterload and potentially offers extra effects with conventional vasodilators that primarily target arteriolar resistance and/or venous tone.
 

References

1. Swedberg K, Komajda M, Böhm M, et al. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomized, placebo controlled study. Lancet 2010; 376: 875-885
2. Böhm M, Swedberg K, Komajda M, et al., SHIFT Investigators. Heart rate as a risk factor in chronic heart failure (SHIFT):the association between heart rate and outcomes in a randomised placebo-controlled trial. Lancet. 2010; 376 :886-94.
3. Ekman I, Chassany O, Komajda M et al. Heart rate reduction with ivabradine and health related quality of life in patients with chronic heart failure: results from the SHIFT study. Eur Heart J 2011; 32: 2395-2404.
4. Tardif JC, O'Meara E, et al. Effects of selective heart rate reduction with ivabradine on left ventricular remodelling and function: results from the SHIFT echocardiography substudy. Eur Heart J 2011; 32: 2507-55.
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6. Kelly RP, Ting CT, Yang TM et al. Effective arterial elastance as index of arterial vascular load in humans. Circulation 1992; 86:513-5 21.EPTED MANUSCRIPT
7. Reil JC, Reil GH, Böhm M. Heart rate reduction by I(f)-channel inhibition and its potential role in heart failure with reduced and preserved ejection fraction. Trends Cardiovasc Med 2009;19:152-157
8. Reil JC, Hohl M, Reil GH et al. Heart rate reduction by If-inhibition improves vascular stiffness and left ventricular systolic and diastolic function in a mouse model of heart failure with preserved ejection fraction. Eur Heart J 2012 doi: 10.1093/eurheartj/ehs
9. Reil JC, Hohl M, Reil GH et al. Heart rate reduction by If-inhibition improves vascular stiffness and left ventricular systolic and diastolic function in a mouse model of heart failure with preserved ejection fraction. Eur Heart J 2012 doi: 10.1093/eurheartj/ehs218
10.Borlaug BA, Heart Rate Reduction:It’s not just for ventricles anymore, Journal of the American College of Cardiology (2013), doi: 10.1016/j.jacc.2013.07.028
 

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